Department of Basic Medicine, Xinjiang Medical University and Xinjiang Key Laboratory of Molecular Biology of Endemic Diseases, Urumqi, Xinjiang 830017, P.R. China.
Department of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang 830017, P.R. China.
Int J Oncol. 2022 Jul;61(1). doi: 10.3892/ijo.2022.5373. Epub 2022 May 26.
Cervical cancer (CC), an aggressive form of squamous cell carcinoma, is characterized by early‑stage lymph node metastasis and an extremely poor prognosis. The authors have previously demonstrated that patients with CC have aberrant glycolysis. The upregulation of receptor for activated C kinase 1 (RACK1) is associated with CC lymph node metastasis (LNM). However, its role in mediating aerobic glycolysis in CC LNM remains unclear. In the present study, H nuclear magnetic resonance analysis revealed a significant association between RACK1 expression and the glycolysis/gluconeogenesis pathway. Additionally, knockdown inhibited aerobic glycolysis and lymphangiogenesis and suppressed CC LNM . Furthermore, protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling was identified as a critical RACK1‑regulated pathway that increased lymphangiogenesis in CC. Co‑immunoprecipitation, immunofluorescence and western blot analysis revealed that RACK1 activated AKT/mTOR signaling by interacting with insulin‑like growth factor 1 receptor (IGF1R). POU class 2 homeobox 2 (POU2F2) bound to the promoter and regulated its transcription, thereby functionally contributing to glycolysis and lymphangiogenesis in CC. Of note, the administration of 2‑deoxy‑D‑glucose, which attenuates glycolysis, inhibited RACK1‑induced lymphangiogenesis in CC. The correlations between RACK1, IGF1R, POU2F2 and hexokinase 2 were further confirmed in CC tissues. Thus, RACK1 plays a crucial role in CC tumor LNM by regulating glycolysis via IGF1R/AKT/mTOR signaling. Thus, the targeting of the POU2F2/RACK1/IGF1R/AKT/mTOR signaling pathway may provide a novel treatment strategy for CC.
宫颈癌（CC）是一种侵袭性的鳞状细胞癌，其特征是早期淋巴结转移和预后极差。作者之前已经证明，宫颈癌患者存在异常糖酵解。受体激活蛋白激酶 C 激酶 1（RACK1）的上调与宫颈癌淋巴结转移（LNM）有关。然而，其在介导宫颈癌 LNM 中的有氧糖酵解作用尚不清楚。在本研究中，H 磁共振分析显示 RACK1 表达与糖酵解/糖异生途径之间存在显著关联。此外， 敲低抑制有氧糖酵解和淋巴管生成 并抑制宫颈癌 LNM 。此外，蛋白激酶 B（AKT）/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路被鉴定为 RACK1 调节的关键通路，该通路增加了宫颈癌中的淋巴管生成。共免疫沉淀、免疫荧光和 Western blot 分析显示，RACK1 通过与胰岛素样生长因子 1 受体（IGF1R）相互作用激活 AKT/mTOR 信号通路。POU 类 2 同源盒 2（POU2F2）结合到 启动子并调节其转录，从而在宫颈癌的糖酵解和淋巴管生成中发挥功能。值得注意的是，抑制糖酵解的 2-脱氧-D-葡萄糖抑制了 RACK1 诱导的宫颈癌中的淋巴管生成。在宫颈癌组织中进一步证实了 RACK1、IGF1R、POU2F2 和己糖激酶 2 之间的相关性。因此，RACK1 通过 IGF1R/AKT/mTOR 信号通路调节糖酵解在宫颈癌肿瘤 LNM 中发挥关键作用。因此，靶向 POU2F2/RACK1/IGF1R/AKT/mTOR 信号通路可能为宫颈癌提供一种新的治疗策略。
